Epilepsy patients with brain tumour may fare better with levetiracetam vs valproic acid

Levetiracetam may be preferable to valproic acid for the first‐line treatment of epilepsy in patients with glioma, with an observational study showing that the former has a more favourable efficacy but similar level of toxicity.

“Potential drug interactions between antiepileptic drugs (AEDs) and chemotherapeutic drugs complicate seizure management in patients with glioma,” according to a team of investigators from the Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands. [Lancet Oncol 2014;15:e395-403]

“[T]herefore, cytochrome P450 (CYP450) enzyme–inducing AEDs, such as phenytoin and carbamazepine, are generally not advised. The choice of AED depends on physicians’ experience as the published literature lacks high‐quality comparative effectiveness studies,” they added.

In the current analysis, the team directly compared two of the most prescribed first‐line AEDs in patients with glioma, namely levetiracetam and valproic acid. They matched patients using either drug on measured potential confounders to mimic the randomized controlled trial design as much as possible.

The total population included 429 levetiracetam users and 429 valproic acid users. Most of them (81 percent) were aged >40 years, and more than 60 percent were men. The patients were followed for a median of 86.2 months (95 percent CI, 76.2–96.2).

Median overall survival was similar in the two groups (26.7 months, 95 percent confidence interval [CI], 21.4–32.0 vs 26.9 months, 95 percent CI, 21.6–32.2, respectively; p=0.699). Competing risks models revealed that the cumulative incidence of treatment failure for any reason was much lower on levetiracetam than on valproic acid (12 months: 33 percent, 95 percent CI, 29–38 vs 50 percent, 95 percent CI, 45–55; p<0.001). [Epilepsia 2021;doi:10.1111/epi.16880]

When looking at specific reasons of treatment failure, failure due to uncontrolled seizures occurred less frequently with levetiracetam (12 months: 16 percent, 95 percent CI, 12–19 vs 28 percent, 95 percent CI, 23–32; p<0.001).

There was no obvious difference in the frequency of treatment failure due to adverse effects (12 months: 14 percent, 95 percent CI, 11–18 vs 15 percent, 95 percent CI, 11–18; p=0.636). The three most common intolerable events were agitation (19 percent), fatigue (9 percent), and somnolence (8 percent) with levetiracetam; and decreased platelet count (14 percent), weight gain (10 percent), and tremor (10 percent) with valproic acid.

“Several factors need to be taken into consideration when interpreting these results,” the investigators said.

“Median dosage at the time of treatment failure due to uncontrolled seizures was significantly higher for levetiracetam. This might indicate less adequate dose escalation of valproic acid, given that both drugs have similar defined daily dosages, which may partly explain the higher percentage of treatment failure due to uncontrolled seizures of valproic acid,” they explained.

The team added that the fact that median dosage of valproic acid was lower when treatment failure due to uncontrolled seizures occurred might be attributed to the narrower therapeutic index of the drug, the unpredictable relationship between dosage and serum concentration, and a possible preference of physicians for levetiracetam.

“Due to its lack of hepatic metabolism and no known pharmacological interactions, physicians might have prematurely added levetiracetam as second‐line AED. Treatment failure due to adverse effects could also be attributed to other medications, such as dexamethasone or chemotherapeutic agents,” they added.

“Given that our study was not designed under ideal circumstances (ie, no randomization, not placebo controlled, no blinding), this study should be interpreted as an effectiveness study and not as an efficacy trial,” according to the investigators.